Cardiovascular disease is the greatest cause of morbidity and mortality in the industrialized world. It not only strikes down a significant fraction of the population without warning but also causes prolonged suffering and disability in an even larger number. Sudden cardiac death (SCD) is prevalent in the population, however it is difficult to treat because it is difficult to predict in which individuals it will occur, and it often occurs without warning, in an out of a hospital setting. It is widely acknowledged that use of implantable cardioverter defibrillators has reduced the incidence of SCD in high risk patients.
With reference to FIGS. 1a and 1b, an implantable cardioverter defibrillator (ICD) 100 is an implantable device that detects the initiation of arrhythmias, such as ventricular tachycardia or fibrillation, and terminates them by delivery of one or more electrical impulses to the heart 102. Often the energy of these impulses is quite large compared to the energy of impulses delivered by an artificial pacemaker, which is used to pace the heart but not to terminate arrhythmias. The increased ease of ICD implantation as well as advances in ICD technology has led to a rapid growth in the rate of ICD implantation. However, ICDs generally are used to terminate an arrhythmia, such as ventricular tachycardia or fibrillation, only after the arrhythmia has started. This feature of ICD function may lead to patients losing consciousness once the arrhythmia starts and also leads to patients experiencing what may be very uncomfortable electrical discharges of the ICD. Frequent ICD discharge can lead to extreme psychological stress in many patients. Some patients have an ICD placed, only to suffer recurrent shocks and finally to have the device deactivated. (Stevenson W. G., et al., “Prevention of Sudden Death in Heart Failure”, J. Cardiovasc Electrophysiol 2001; 12:112-4. The contents of this article and all articles cited below are hereby incorporated by reference into the present application as if reproduced in their entireties.) Recently, it was shown that a rapid and progressive electrophysiological deterioration during ventricular fibrillation that may explain the decreased probability of successful resuscitation after prolonged fibrillation. (Tovar O. H., et al., “Electrophysiological Deterioration During Long-Duration Ventricular Fibrillation”, Circulation 2000; 102:2886-91) Also, the more often the ICD discharges, the shorter is the life of its battery. Frequent ICD discharge can also damage the heart tissue itself and as a result may make the heart more susceptible to future arrhythmias. Thus it would be highly desirable to be able to be able to prevent arrhythmias from starting rather than terminating them after their initiation by administration of an electrical shock.
Arrhythmias such as ventricular tachycardia and fibrillation are often caused by an electrical mechanism called reentry. With reference to FIGS. 2A-2D, reentry involves a loop-like path of electrical activation 104 circulating through a region of heart tissue, re-entering regions 106 that had been previously activated in prior loops. In early ischemic arrhythmias, ventricular tachycardia and fibrillation have been shown to depend on reentrant excitation. Although reentrant excitation is thought to underlie a variety of benign and malignant cardiac rhythms, descriptions of the mechanisms that are involved in the development of reentry remain obscured. A major factor leading to the genesis of ventricular fibrillation during ischemia is dispersion of refractoriness. Dispersion of refractoriness is a measure of non-homogeneous recovery of excitability in a given mass of cardiac tissue (tissue is called refractory when it can not be re-stimulated until it has recovered). In normal myocardium the excitability is strictly proportional to the duration of repolarization. Reentry is the most likely mechanism of arrhythmia facilitated by enhanced dispersion of repolarization. The elements that are most often represented in the experimental or clinical models of arrhythmias attributed to reentry include non-uniform conduction, non-uniform excitability, and non-uniform refractoriness.
Ischemia alters refractoriness through its effects on resting potential and action potential duration. These effects are non-uniform during regional ischemia because of local variations in blood flow and diffusion of substrate and metabolites across the ischemic boundary. The resulting non-uniformity in refractoriness undoubtedly contributes to the increased vulnerability of an ischemic heart to fibrillation. An important mechanism for enhancing dispersion of refractory period is alternation of the action potential from beat to beat.
Action potential alternans involves an alternating sequence in which the shape of the action potential (the wave-like pattern of variation of a cell's transmembrane potential) associated with an individual cardiac cell changes on an every other beat basis (as shown in FIG. 3 between beat 108 and beat 110). If the duration of the action potential alternates on an every other beat basis, then the duration of refractory period also alternates in duration because the refractory period is generally roughly comparable to the duration of the action potential. Thus action potential alternans creates a situation in which a region of the myocardium has a long refractory period on an every other beat basis. On these alternate beats, a region with action potential alternans can create islands of refractory tissue that can cause fractionation of activation wavefronts. Thus, action potential alternans, which generally occurs in diseased tissue, can promote the development of reentry.
The presence of action potential alternans can be detected in an electrocardiogram as ST segment and/or T-wave alternans (repolarization alternans—see representative portions 112 and 114 of heart beats depicted in FIG. 4). In the surface electrocardiogram (ECG), repolarization alternans, has been correlated with the presence of ventricular vulnerability to arrhythmias in humans. In this application, we define repolarization alternans to be any change in the morphology of the ST segment or T-wave of the electrocardiogram occurring on an every other beat basis.
Computer simulations of cardiac conduction processes in the inventors' laboratory predicted the relationship between the presence of electrical alternans and enhanced susceptibility to the onset of reentrant rhythm disturbances. (Smith, J. M., Cohen, R. J., “Simple finite-element model accounts for wide range of cardiac dysrhythmias”, Proc Natl Acad Sci 1984; 81:233-7.)
Specifically, the simulated ECGs have shown electrical alternans in myocardial cells that have refractory periods that exceed a threshold cycle length and as a result there will be a corresponding subpopulation of cells that can be at most be activated every second beat. This is reflected in electrical alternans in the ECG illustrated in FIG. 4. This process leads to wave-front fractionation thus being the predisposing factor to reentrant ventricular dysrhythmias.
Electrical alternans have been shown to precede ventricular fibrillation in dogs. (Smith, J M, et al., “Electrical alternans and cardiac electrical instability”, Circulation 1988, 77:110-21; Nearing, B D, et al., “Dynamic tracking of cardiac vulnerability by complex demodulation of the T wave”, Science 1991, 252:437-40.) A computer algorithm developed by the inventors that is sensitive to microvolt level oscillations of the surface ECG, in a series of animal experiments, revealed that coronary artery occlusion was also uniformly accompanied by a decrease in electrical stability (as measured by the ventricular fibrillation threshold) and occlusion was frequently accompanied by an increase in the observed alternation in ECG vector morphology. A description of the algorithm, which may be employed in the present invention for estimating repolarization alternans, and the noted results may be found in the following references: Smith, J. M., and Cohen, R. J., “Simple finite-element model accounts for wide range of cardiac dysrhythmias”, Proc Natl Acad Sci USA 1984, 81:233-7; Adam, D. R., et al., “Fluctuations in T-wave morphology and susceptibility to ventricular fibrillation”, J. Electrocardiol 1984, 17:209-18; and Clancy, E. A., et al., “A simple electrical-mechanical model of the heart applied to the study of electrical-mechanical alternans”, IEEE Trans Biomed Eng 1991, 38:551-60.
In humans, alternation in electrical repolarization processes in the heart has been associated with increased vulnerability to ventricular arrhythmias under diverse pathophysiologic conditions such as myocardial ischemia (See Dilly, S. G., et al., “Electrophysiological alternans and restitution during acute regional ischaemia in myocardium of anaesthetized pig”, J Physiol (London) 1988, 402:315-33; Dilly, S. G., et al., “Changes in monophasic action potential duration during the first hour of regional myocardial ischaemia in the anaesthetised pig”, Cardiovasc Res 1987, 21:908-15; Lewis, T., “Notes upon alternation of the heart”, Q J Med 1910, 4:141-144; Salerno, J. A., et al., “Ventricular arrhythmias during acute myocardial ischaemia in man. The role and significance of R-ST-T alternans and the prevention of ischaemic sudden death by medical treatment”, Eur Heart J 1986, 7 Suppl A:63-75.), Prinzmetal's angina (See Kleinfeld, M. J., et al., “Alternans of the ST segment in Prinzmetal's angina”, Circulation, 1977, 55:574-7; Reddy, C. V., et al., “Repolarization alternans associated with alcoholism and hypomagnesemia”, Am. J. Cardiol., 1984, 53:390-1), altered autonomic state (See Nearing, B. D., et al., “Potent antifibrillatory effect of combined blockade of calcium channels and 5-HT2 receptors with nexopamil during myocardial ischemia and reperfusion in dogs: comparison to diltiazem”, J. Cardiovasc. Pharmacol., 1996, 27:777-87; Cheng, T. C., “Electrical alternans. An association with coronary artery spasm”, Arch. Intern. Med., 1983, 143:1052-3; Kaufman, E. S., et al., “Influence of heart rate and sympathetic stimulation on arrhythmogenic T wave alternans”, Am. J. Physiol. Heart Circ. Physiol. 2000; 279:H1248-55), electrolyte abnormalities (See Reddy; Kaufman; Shimoni, Z, et al., “Electrical alternans of giant U waves with multiple electrolyte deficits”, Am. J. Cardiol. 1984, 54:920-1), and the long QT syndrome (See Schwartz, P. J., et al., “Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome”, Am. Heart. J., 1975, 89:45-50; Platt, S. B., et al., “Occult T wave alternans in long QT syndrome”, J. Cardiovasc. Electrophysiol., 1996, 7:144-8; Armoundas, A. A., et al., “Images in cardiovascular medicine. T-wave alternans preceding torsade de pointes ventricular tachycardia”, Circulation, 2000, 101:2550). Repolarization alternans in the form of macroscopically visible TWA has been associated anecdotally with a variety of conditions associated with an increased risk of ventricular arrhythmias (See H. H., et al., “Electrical alternans”, NY State J Med 1948, 1:1164-1166; Kleinfeld, M, et al., “Pacemaker alternans: a review”, Pacing Clin. Electrophysiol., 1987, 10:924-33; Calabrese, G, et al., “ST-T segment alternans in ventricular tachycardia associated with inversion of the U wave in Prinzmetal angina during exercise test. Description of a clinical case”, G. Ital. Cardiol., 1990, 20:239-41; Cinca, J, et al., “The dependence of T wave alternans on diastolic resting period duration”, Eur. J. Cardiol., 1978, 7:299-309; Costello, D L, et al., “Echocardiographic examination in left ventricular alternans”, Chest, 1979, 75:72-5; Fisch, C, et al., “T wave alternans: an association with abrupt rate change”, Am. Heart 1, 1971, 81:817-21; Hashimoto, H, et al., “Potentiating effects of a ventricular premature beat on the alternation of the ST-T complex of epicardial electrograms and the incidence of ventricular arrhythmias during acute coronary occlusion in dogs”, J. Electrocardiol., 1984, 17:289-301; Hashimoto, H, et al., “Effects of calcium antagonists on the alternation of the ST-T complex and associated conduction abnormalities during coronary occlusion in dogs”, Br. J. Pharmacol., 1981, 74:371-80; Konta, T, et al., “Significance of discordant ST alternans in ventricular fibrillation”, Circulation, 1990, 82:2185-9; Puletti, M, et al., “Alternans of the ST segment and T wave in acute myocardial infarction”, J. Electrocardiol., 1980, 13:297-300.
Microvolt level T-wave alternans was first reported in 1982. (See Adam, D. R., et al., “Ventricular fibrillation and fluctuations in the magnitude of the repolarization vector”, IEEE Computers Cardiol., 1982, 241-244.) Subsequently, a series of studies led to the development of a spectral method to detect subtle microvolt level repolarization alternans, and developed a relationship between alternans and ventricular fibrillation thresholds in animal studies and susceptibility to ventricular arrhythmias in humans undergoing EPS testing. (See Smith; Adam; Ritzenberg, A. L., et al., “Period multupling-evidence for nonlinear behaviour of the canine heart”, Nature, 1984, 307:159-61.) These studies experimentally linked repolarization alternans to increased susceptibility to ventricular tachyarrhythmias.
Recent studies have demonstrated that the presence of microvolt level repolarization alternans (generally not visible upon visual inspection of the electrocardiogram, but detectable using advanced signal processing techniques such as described in: Smith; Clancy; Platt; Rosenbaum, D. S., et al., “Electrical alternans and vulnerability to ventricular arrhythmias”, N. Engl. J. Med., 1994, 330:235-41; and Rosenbaum, D. S., et al., “Predicting sudden cardiac death from T wave alternans of the surface electrocardiogram: promise and pitfalls”, J. Cardiovasc. Electrophysiol., 1996, 7:1095-111), is associated with an increased risk of ventricular arrhythmias and sudden cardiac death. (See Verrier, R. L., et al., “Electrophysiologic basis for T wave alternans as an index of vulnerability to ventricular fibrillation”, J. Cardiovasc. Electrophysiol., 1994, 5:445-61; Verrier, R. L., et al., “Life-threatening cardiovascular consequences of anger in patients with coronary heart disease”, Cardiol. Clin., 1996, 14:289-307; Nearing, B. D., et al., “Personal computer system for tracking cardiac vulnerability by complex demodulation of the T wave”, J. Appl. Physiol., 1993, 74:2606-12; and Nearing, B. D., et al., “Quantification of ischaemia induced vulnerability by precordial T wave alternans analysis in dog and human”, Cardiovasc. Res., 1994, 28:1440-9).
In ECG tracings obtained from Holter monitoring, there has been evidence that repolarization alternans persist for long periods before the onset of an unstable heart rhythm like ventricular tachycardia or ventricular fibrillation (See Armoundas, A. et al., “Images in cardiovascular medicine. T-wave alternans preceding torsade de pointes ventricular tachycardia”, Circulation 2000; 101:2550.)
Thus, in both computer simulations and experimental reports electrical alternans has been shown to increase its magnitude in the stage preceding a malignant heart rhythm like ventricular fibrillation.
From the time heart rate variability (HRV) was first appreciated as a harbinger of sudden cardiac death in post myocardial infarction patients by Wolf et al. (Wolf, M. M., et al., “Sinus arrhythmia in acute myocardial infarction”, Med. J. Aust. 1978, 2:52-3), numerous studies have established a significant relationship between HRV and susceptibility to lethal ventricular arrhythmias. (See Kleiger, R. E., et al., “Decreased heart rate variability and its association with increased mortality after acute myocardial infarction”, Am. J. Cardiol., 1987, 59:256-62; Malik, M, et al., “Heart rate variability in relation to prognosis after myocardial infarction: selection of optimal processing techniques”, Eur. Heart J., 1989, 10:1060-74; Bigger, J. T., et al., “Frequency domain measures of heart period variability and mortality after myocardial infarction”, Circulation, 1992, 85:164-71; and Fallen, E. L., et al., “Spectral analysis of heart rate variability following human heart transplantation: evidence for functional reinnervation”, J. Auton. Nerv. Syst., 1988, 23:199-206.) A major issue has been how to describe HRV mathematically. The phenomenon of fluctuations in the interval between consecutive heart beats has been the subject of investigations using a wide range of methodologies including time domain (See Adamson, P. B., et al., “Unexpected interaction between beta-adrenergic blockade and heart rate variability before and after myocardial infarction. A longitudinal study in dogs at high and low risk for sudden death”, Circulation, 1994, 90:976-82; and “Electrophysiology TfotEsocatNASoPa. Heart rate variability, standards of measurement, physiological interpretation and clinical use”, Circulation, 1996, 93:1043-1065), frequency domain (See Bigger, J. T., et al., “Predicting mortality after myocardial infarction from the response of RR variability to antiarrhythmic drug therapy”, J. Am. Coll. Cardiol., 1994, 23:733-40; and Huikuri, H. V., et al., “Power-law relationship of heart rate variability as a predictor of mortality in the elderly”, Circulation, 1998, 97:2031-6), geometric (Malik, M, et al., “Influence of the recognition artefact in automatic analysis of long-term electrocardiograms on time-domain measurement of heart rate variability”, Med. Biol. Eng. Comput., 1993, 31:539-44), and non-linear (See Schmidt, G, et al., “Nonlinear methods for heart rate variability”, In: Malik M, Camm A J, eds. Heart Rate Variability. Armonk, N.Y.: Futura, 1995:87-98; Kanters, J. K., et al., “Short- and long-term variations in non-linear dynamics of heart rate variability”, Cardiovasc. Res., 1996, 31:400-9; and Kanters, J. K., et al., “Lack of evidence for low-dimensional chaos in heart rate variability. J Cardiovasc Electrophysiol 1994; 5:591-601), methods. With the general recognition of nonlinear dynamics theory in the mid 80's, it was proposed that HRV should be viewed as the result of nonlinear determinism in the regulatory systems governing the heart rate. Parameters indicative of possible low-dimensional nonlinear determinism include Lyapunov exponents, strange attractors and correlation dimensions (Grassberger, P, et al., “Measuring the strangeness of strange attractors”, Physica D., 1983, 9:183-208). For example, it has been suggested that the correlation dimension (CD) could be used to distinguish patients who develop ventricular fibrillation during the monitoring period from those who do not. (See Chon, K. H., et al., “Modeling nonlinear determinism in short time series from noise driven discrete and continuous systems”, Int. J. Bifurcation & Chaos, 2000, 10:2745-2766.)
While ICDs currently are an effective therapy for the termination of heart rhythm disturbances (See Prystowsky, E. N., “Screening and therapy for patients with nonsustained ventricular tachycardia”, Am. J. Cardiol., 2000, 86:K34-K39; Buxton, A. E., et al., “Nonsustained ventricular tachycardia”, Cardiol. Clin., 2000, 18:327-36, viii; and Buxton, A. E., et al., “Electrophysiologic testing to identify patients with coronary artery disease who are at risk for sudden death—Multicenter Unsustained Tachycardia Trial Investigators”, N. Engl. J. Med., 2000, 342:1937-45), their role is to deliver electrical impulses to terminate the arrhythmia rather than to prevent its onset. Thus, patients are being subjected to a serious arrhythmia for a period of time until therapy is delivered. Also, delivery of electrical impulses from the ICD may be painful and may damage the heart.
There remains, therefore, a need to prevent arrhythmias from initiating rather than treating them with what may be much higher energy electrical pulses after the arrhythmias have been initiated.
A key question underlying the control of alternans is to design perturbations that stabilize the system about one of the unstable equilibrium states of the system (Shinbrot T, Ott E, Grebogi C, et al. Using chaos to direct trajectories to targets. Physical Review Letters. Dec. 24, 1990; 65(26):3215-3218). The corresponding unstable equilibrium state is a 1:1 (period 1) pattern, for which the local APD is the same for each stimulus. That is, by making small real-time adjustments to the pacing interval, based on measurements of the APD or the QT interval if it refers to adjustments of the whole heart, one should be able to achieve this state. One approach that has been applied successfully in predictably controlling the APD (shortening/prolonging by application of a negative/positive amplitude pulse or cathodic/anodic stimulus) involved the employment of electrical stimuli delivered during the absolute refractory period (Brunckhorst C B, Shemer I, Mika Y, et al. Cardiac contractility modulation by non-excitatory currents: studies in isolated cardiac muscle. Eur J Heart Fail. January 2006; 8(1):7-15; Augello G, Santinelli V, Vicedomini G, et al. Cardiac contractility modulation by non-excitatory electrical currents. The new frontier for electrical therapy of heart failure. Ital Heart J. June 2004; 5 Suppl 6:68S-75S; Pappone C, Augello G, Rosanio S, et al. First human chronic experience with cardiac contractility modulation by nonexcitatory electrical currents for treating systolic heart failure: mid-term safety and efficacy results from a multicenter study. J Cardiovasc Electrophysiol. April 2004; 15(4):418-427; Pappone C, Rosanio S, Burkhoff D, et al. Cardiac contractility modulation by electric currents applied during the refractory period in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. Dec. 15, 2002; 90(12):1307-1313; Pappone C, Vicedomini G, Salvati A, et al. Electrical modulation of cardiac contractility: clinical aspects in congestive heart failure. Heart Fail Rev. January 2001; 6(1):55-60).